JP5281887B2 - Combination of pyrimidylaminobenzamide compound and imatinib for the treatment or prevention of proliferative diseases - Google Patents

Abstract

The invention provides a pharmaceutical combination comprising: a) a pyrimidylaminobenzamide compound, and b) imatinib. and a method for treating or preventing a proliferative disease, especially GIST, using such a combination.

Description

The present invention relates to (a) a pyrimidylaminobenzamide derivative compound and (b) 4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3- (4-pyridin-3-yl) pyrimidine 2-ylamino) phenyl] - benzamide (Gleevec (TM) pharmaceutical combination comprising imatinib) sold under the name, and, proliferative diseases, most preferably for the treatment of gastrointestinal stromal tumors (GIST) Relating to the use of such combinations.

Gastrointestinal stromal tumor (GIST) is a recently-characterized family of mesenchymal neoplasms, which gastrointestinal tract, most commonly begins from the stomach (60 to 70% of the total GIST). In the past, these tumors were variously classified as leiomyomas, leiomyoblastomas, or leiomyosarcomas. However, it is now clear that GIST represents a clear clinicopathological set of diseases based on molecular etiology and clinical characteristics. GIST occurs most commonly in middle-aged or elderly people, with a median age at examination in the 50s-60s and no significant gender difference in incidence. At least 10-30% of GIST is malignant, resulting in intraperitoneal diffusion and metastasis, most commonly found in liver and peritoneal dissemination. Malignant GIST occurs with a frequency of about 0.3 new cases per 100.000 per year. The most common symptom is vague upper abdominal pain. Most (30%) are asymptomatic and GIST can be diagnosed during the assessment of anemia due to tumor-related gastrointestinal bleeding.

  Management of metastatic and inoperable GIST is a major problem because it is well known that GIST is unresponsive to cancer chemotherapy. For example, in one recent Phase II trial, 12 out of 18 (67%) patients with advanced leiomyosarcoma responded to a regimen consisting of dacarbazine, mitomycin, doxorubicin, cisplatin, and sargramostim, but GIST Only 1 out of 21 (5%) responded (J. Edmonson, R. Marks, J. Buckner, M. Mahoney, Proc. Am. Soc. Clin. Oncol. 1999; 18: 541a “Contrast of response to D-MAP + sargramostin between patients with advanced malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas ”). Treatment results remain equally impressive with other chemotherapy regimens. Consistent with clinical chemical resistance, the expression of P-glycoprotein and multidrug resistance protein MRP1 associated with multidrug resistance (MDR) is promoted in malignant GIST compared to leiomyosarcoma.

  Despite the many treatment options for patients with proliferative diseases, there remains a need for effective and safe anti-proliferative agents and their preferential use in combination therapy.

  It has surprisingly been demonstrated by the present invention that GIST can be fully treated with pyrimidylaminobenzamide derivatives or pharmaceutically acceptable salts thereof alone or in combination with imatinib.

SUMMARY OF THE INVENTION According to the present invention, a combination comprising (a) at least one pyrimidylaminobenzamide compound and (b) imatinib, such as those defined below, has beneficial effects on proliferative diseases such as tumors, especially GIST. Turned out to be.

〔式中、
Ｒ_１は水素、低級アルキル、低級アルコキシ−低級アルキル、アシルオキシ−低級アルキル、カルボキシ−低級アルキル、低級アルコキシカルボニル−低級アルキル、またはフェニル−低級アルキルであり；
Ｒ_２は水素、所望により１個以上の同一または異なる基Ｒ_３で置換されていてよい低級アルキル、シクロアルキル、ベンズシクロアルキル、ヘテロシクリル、アリール基、または０個、１個、２個もしくは３個の環窒素原子および０個もしくは１個の酸素原子および０個もしくは１個の硫黄原子を含む単または二環式ヘテロアリール基であり、この基はいずれの場合も非置換であるか一または多置換されており；
そしてＲ_３はヒドロキシ、低級アルコキシ、アシルオキシ、カルボキシ、低級アルコキシカルボニル、カルバモイル、Ｎ−モノ−またはＮ,Ｎ−ジ置換カルバモイル、アミノ、モノ−またはジ置換アミノ、シクロアルキル、ヘテロシクリル、アリール基、または０個、１個、２個もしくは３個の環窒素原子および０個もしくは１個の酸素原子および０個もしくは１個の硫黄原子を含む単または二環式ヘテロアリール基であり、この基はいずれの場合も非置換であるか一または多置換されており；
またはＲ_１およびＲ_２が一緒になって、所望により低級アルキル、シクロアルキル、ヘテロシクリル、フェニル、ヒドロキシ、低級アルコキシ、アミノ、モノ−またはジ置換アミノ、オキソ、ピリジル、ピラジニルまたはピリミジニルでモノ−またはジ置換されていてよい、４個、５個または６個の炭素原子のアルキレン；４個または５個の炭素原子を有するベンズアルキレン；１個の酸素と３個または４個の炭素原子を有するオキサアルキレン；または１個の窒素および３個または４個の炭素原子を含むアザアルキレン(ここで、窒素は非置換であるか、または、低級アルキル、フェニル−低級アルキル、低級アルコキシカルボニル−低級アルキル、カルボキシ−低級アルキル、カルバモイル−低級アルキル、Ｎ−モノ−またはＮ,Ｎ−ジ置換カルバモイル−低級アルキル、シクロアルキル、低級アルコキシカルボニル、カルボキシ、フェニル、置換フェニル、ピリジニル、ピリミジニル、またはピラジニルで置換されている)であり；
Ｒ_４は水素、低級アルキル、またはハロゲンである。〕
のピリミジルアミノベンズアミド化合物およびそのような化合物のＮ−オキシドまたは薬学的に許容される塩の使用に関する。 DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of formula (I) for the manufacture of a pharmaceutical composition for the treatment of kinase dependent diseases:

[Where,
R ₁ is hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl;
R ₂ is hydrogen, optionally a lower alkyl, cycloalkyl, benzcycloalkyl, heterocyclyl, aryl group, or 0, 1, 2, or 3 optionally substituted with one or more of the same or different groups R ₃ A mono- or bicyclic heteroaryl group containing a ring nitrogen atom and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which in each case is unsubstituted, mono- or poly- Has been replaced;
And R ₃ is hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N, N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, aryl group, or A mono- or bicyclic heteroaryl group containing 0, 1, 2 or 3 ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, Are also unsubstituted or mono- or polysubstituted;
Or R ₁ and R _{2 taken} together are optionally mono- or di-lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl. Optionally substituted alkylene of 4, 5 or 6 carbon atoms; benzalkylene having 4 or 5 carbon atoms; oxaalkylene having 1 oxygen and 3 or 4 carbon atoms Or an azaalkylene containing 1 nitrogen and 3 or 4 carbon atoms, where the nitrogen is unsubstituted or lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy- Lower alkyl, carbamoyl-lower alkyl, N-mono- or N, N-di-position Substituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl);
R ₄ is hydrogen, lower alkyl, or halogen. ]
And the use of N-oxides or pharmaceutically acceptable salts of such compounds.

The terms used above and below preferably have the following meanings within the context of the present specification unless otherwise indicated:
The prefix “lower” means a radical having a maximum of 7 (including 7), in particular a maximum of 4 (including 4) carbon atoms, which radical may be straight or branched in one or more places. You may do it.

  When the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, and the like.

  All asymmetric carbon atoms can be present in the (R)-, (S)-or (R, S) -configuration, preferably in the (R)-or (S) -configuration. The compounds can therefore exist as a mixture of isomers or as pure isomers, preferably as enantiomerically pure diastereomers.

The invention also relates to possible tautomers of the compounds of formula I.
Lower alkyl is preferably from 1 to (including 1) to 7 (including 7), preferably from 1 to (including 1) to 4 (including 4) Alkyl, which is a chain or branched chain; preferably, lower alkyl is n-butyl, sec-butyl, butyl such as isobutyl, tert-butyl, propyl such as n-propyl or isopropyl, ethyl or methyl . Preferably lower alkyl is methyl, propyl or tert-butyl.
Lower acyl is preferably formyl or lower alkylcarbonyl, especially acetyl.

An aryl group is an aromatic radical that is attached to the molecule through a bond located at the aromatic ring carbon atom of the radical. In preferred embodiments, aryl is an aromatic radical having 6 to 14 carbon atoms, especially phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrenyl, and unsubstituted or especially amino, mono- or disubstituted amino. Halogen, lower alkyl, substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbamoyl, N-mono- or N, N-disubstituted carbamoyl, amidino, guanidino, ureido, mercapto, sulfo, lower alkylthio, phenylthio, phenyl-lower alkylthio, lower alkylphenylthio, lower alkylsulfinyl Halogen-lower alkyl such as phenylsulfinyl, phenyl-lower alkylsulfinyl, lower alkylphenylsulfinyl, lower alkylsulfonyl, phenylsulfonyl, phenyl-lower alkylsulfonyl, lower alkylphenylsulfonyl, halogen-lower alkyl mercapto, especially trifluoromethanesulfonyl Selected from lower alkylenedioxy bonded to the adjacent C atom of the ring, such as sulfonyl, dihydroxybora (—B (OH) ₂ ), heterocyclyl, mono- or bicyclic heteroaryl groups and methylenedioxy; It is substituted with one or more, preferably up to 3, in particular with 1 or 2 substituents. Aryl is more preferably phenyl, naphthyl or tetrahydronaphthyl, which are in each case unsubstituted or halogen, especially fluorine, chlorine or bromine; hydroxy; lower alkyl, for example methyl, halogen-lower Hydroxy, etherified with alkyl, eg trifluoromethyl, or phenyl; lower alkylenedioxy, eg methylenedioxy, lower alkyl, eg methyl or propyl, attached to two adjacent C atoms; halogen- Lower alkyl, such as trifluoromethyl; hydroxy-lower alkyl, such as hydroxymethyl or 2-hydroxy-2-propyl; lower alkoxy-lower alkyl; such as methoxymethyl or 2-methoxyethyl; lower alkoxycarbonyl- Secondary alkyl such as methoxycarbonylmethyl; lower alkynyl such as 1-propynyl; esterified carboxy, especially lower alkoxycarbonyl such as methoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl; N-mono-substituted carbamoyl, especially lower alkyl, For example, carbamoyl monosubstituted by methyl, n-propyl or isopropyl; amino; lower alkylamino, such as methylamino; di-lower alkylamino, such as dimethylamino or diethylamino; lower alkylene-amino, such as pyrrolidino or piperidino; Alkylene-amino such as morpholino, lower azaalkylene-amino such as piperazino, acylamino such as acetylamino or benzoylamino ; Lower alkylsulfonyl, for example methylsulfonyl; sulfamoyl; or one or independently by two substituents selected from the group comprising phenylsulfonyl is substituted.

  The cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl and is unsubstituted or selected from the group defined above as a substituent for one or more, especially 1 or 2 aryls Most preferably substituted with lower alkyl such as methyl, lower alkoxy such as methoxy or ethoxy, or hydroxy, and further with oxo or benzoyl as in benzcyclopentyl or benzcyclohexyl. It may be condensed with a ring.

  Substituted alkyl is alkyl as defined immediately above, especially lower alkyl, preferably methyl; here, mainly halogen, especially fluorine, amino, N-lower alkylamino, N, N-di-lower alkylamino, N-lower There may be substituents of one or more, in particular up to 3, of the groups selected from alkanoylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl-lower alkoxycarbonyl. Trifluoromethyl is particularly preferred.

  Mono- or di-substituted amino is especially lower alkyl such as methyl; hydroxy-lower alkyl such as 2-hydroxyethyl; lower alkoxy lower alkyl such as methoxyethyl; phenyl-lower alkyl such as benzyl or 2-phenylethyl. Lower alkanoyl such as acetyl; benzoyl; substituted benzoyl (wherein the phenyl radical is nitro, amino, halogen, N-lower alkylamino, N, N-di-lower alkylamino, hydroxy, cyano, carboxy, One or more, preferably substituted with one or two substituents selected from lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and phenyl-lower alkoxycarbonyl, wherein the phenyl radical is non- Is a replacement or Or in particular one or more selected from nitro, amino, halogen, N-lower alkylamino, N, N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl, preferably Is substituted with one or two radicals independently selected from each other; and preferably N, such as N-methylamino -Lower alkylamino, hydroxy-lower alkylamino such as 2-hydroxyethylamino or 2-hydroxypropyl, lower alkoxy lower alkyl such as methoxyethyl, phenyl-lower alkylamino such as benzylamino, N, N-di -Lower alkylamino, N-phenyl-lower alkyl-N- Quaternary alkylamino, N, N-di-lower alkylphenylamino, lower alkanoylamino such as acetylamino, or benzoylamino and phenyl-lower alkoxycarbonylamino (in which case the phenyl radical is unsubstituted) Or especially substituted with nitro or amino, and also halogen, amino, N-lower alkylamino, N, N-di-lower alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, carbamoyl or aminocarbonylamino A substituent selected from the group comprising Disubstituted amino is also a lower alkylene-amino such as pyrrolidino, 2-oxopyrrolidino or piperidino; lower oxaalkylene-amino such as morpholino, or lower azaalkylene-amino such as piperazino or N-methylpiperazino or N-methoxycarbonylpiperazino. Such N-substituted piperazino.

  Halogen is especially fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.

Etherified hydroxy is especially C ₈ -C ₂₀ alkyloxy such as n-decyloxy, lower alkoxy (preferred) such as methoxy, ethoxy, isopropyloxy, or tert-butyloxy, phenyl-lower alkoxy such as benzyloxy, Halogen-lower alkoxy, such as phenyloxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or 1,1,2,2-tetrafluoroethoxy, or single or two containing one or two nitrogen atoms Lower alkoxy substituted by cyclic heteroaryl, preferably imidazolyl such as 1H-imidazol-1-yl, benzimidazolyl such as pyrrolyl, 1-benzimidazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl , Especially 2- Pyrimidinyl, pyrazinyl, isoquinolinyl, especially lower alkoxy substituted with 3-isoquinolinyl, quinolinyl, indolyl or thiazolyl.

  Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyloxy such as tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy such as benzyloxycarbonyloxy.

Esterified carboxy is inter alia tert-butoxycarbonyl, isopropoxycarbonyl, lower alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl, phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.
Alkanoyl is primary alkylcarbonyl, especially lower alkanoyl, such as acetyl.

  N-mono- or N, N-disubstituted carbamoyl is, inter alia, lower alkyl, phenyl-lower alkyl and hydroxy-lower alkyl, or lower alkylene, oxa-lower alkylene or terminal aza optionally substituted with nitrogen atoms. Substituted with one or two substituents independently selected from lower alkylene.

  A mono- or bicyclic heteroaryl group containing 0, 1, 2 or 3 ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom (in this case Is also unsubstituted or mono- or polysubstituted) means a heterocyclic moiety that is unsaturated in the ring that connects the heteroaryl radical to the rest of the molecule of formula I and is preferably a ring. In the ring attached here, but optionally also in any annealed ring, at least one carbon atom is replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur Wherein the ring to which it is attached preferably has 5 to 12, more preferably 5 or 6 ring atoms; and is unsubstituted or more than one, especially 1 or With substituents selected from the group as defined above as substituents of number of aryl, most preferably by lower alkyl, such as methyl, lower alkoxy such as methoxy or ethoxy, or may be substituted with hydroxy. Preferably the mono- or bicyclic heteroaryl group is 2H-pyrrolyl, pyrrolyl, imidazolyl, benzoimidazolyl, pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthylidinyl, quinoxalyl , Quinazolinyl, quinolinyl, pteridinyl, indolizinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, furazanyl, benzo [d] pyrazolyl, thienyl and furanyl. More preferably, the mono- or bicyclic heteroaryl group is pyrrolyl, imidazolyl such as 1H-imidazol-1-yl, benzimidazolyl such as 1-benzimidazolyl, indazolyl, especially 5-indazolyl, pyridyl, especially 2-3, -Or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, especially 4- or 8-quinolinyl, indolyl, especially 3-indolyl, thiazolyl, benzo [d] pyrazolyl, thienyl, and Selected from furanyl. In one preferred embodiment of the present invention, the pyridyl radical is substituted with hydroxy in the ortho position relative to the nitrogen atom, and thus is a tautomer that is at least partially pyridine- (1H) 2-one. It exists in a corresponding form. In other preferred embodiments, the pyrimidinyl radical is substituted at both the 2 and 4 positions with hydroxy, and thus as several tautomeric forms, for example as pyrimidine- (1H, 3H) 2,4-dione. Exists.

  Heterocyclyl is a 5-, 6- or 7-membered heterocyclic system having 1 or 2 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, especially unsaturated or fully or May be partially saturated and unsubstituted or substituted, especially with lower alkyl such as methyl, phenyl-lower alkyl such as benzyl, oxo, or heteroaryl such as 2-piperazinyl; Heterocyclyl is especially 2- or 3-pyrrolidinyl, 2-oxo-5-pyrrolidinyl, piperidinyl, N-benzyl-4-piperidinyl, N-lower alkyl-4-piperidinyl, N-lower alkyl-piperazinyl, morpholinyl, such as 2- Or 3-morpholinyl, 2-oxo-1H-azepin-3-yl, 2-the Rahidorofuraniru, or 2-methyl-1,3-dioxolan-2-yl.

Salts are especially pharmaceutically acceptable salts of compounds of formula I.
Such salts are formed, for example, as acid addition salts, preferably from organic or inorganic acids and compounds of the formula I having basic nitrogen atoms, in particular pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic acids, phosphonic acids, sulfonic acids or sulfamic acids, such as acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelin. Acids, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glutamic acid or amino acids such as aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4 -Aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid 1,5-naphthalene-disulfur Acid, 2-, 3- or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or ascorbine Other organic protic acids such as acids.

  In the presence of negatively charged radicals such as carboxy or sulfo, salts are also formed with bases, such as metal or ammonium salts, such as alkali metal or alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts, Or ammonia or an ammonium salt with a suitable organic amine such as a tertiary monoamine such as triethylamine or tri (2-hydroxyethyl) amine, or a heterocyclic base such as N-ethyl-piperidine or N, N′-dimethylpiperazine. is there.

  When a basic group and an acid group are present in the same molecule, the compounds of formula I can also form inner salts.

  For isolation and production purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are used (in the form of pharmaceutical preparations where applicable) and are therefore preferred.

  In view of the close relationship between the novel compound in free form and the novel compound in the form of a salt, including salts used as intermediates, eg, for purification or identification of the novel compound, any references to advantageous compounds above and below are also appropriate. And should be understood as referring to their corresponding salts as long as expected.

の４−メチル−３−[[４−(３−ピリジニル)−２−ピリミジニル]アミノ]−Ｎ−[５−(４−メチル−１Ｈ−イミダゾル−１−イル)−３−(トリフルオロメチル)フェニル]ベンズアミド、および薬学的に許容されるその塩である。 Compounds within the scope of formula (I) and methods for their preparation are disclosed in WO 04/005281 published 15 January 2004, which is incorporated herein by reference. Preferred compounds are those of formula (II):

4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) Phenyl] benzamide, and pharmaceutically acceptable salts thereof.

の化合物４−(４−メチルピペラジン−１−イルメチル)−Ｎ−[４−メチル−３−(４−ピリジン−３−イル)ピリミジン−２−イルアミノ)フェニル]−ベンズアミド(Gleevec(登録商標)の名で市販されているイマチニブ)を含む。 The combination of the present invention has the formula (III):

Of 4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3- (4-pyridin-3-yl) pyrimidin-2-ylamino) phenyl] -benzamide (Gleevec®) Including imatinib, which is commercially available by name.

  The preparation of compounds (III) and their use as antitumor agents in particular is described in Example 21 of European patent application EP-A-0564409 published on October 6, 1993, and corresponding applications in many other countries. And patents such as US Pat. No. 5,521,184 and Japanese Patent 2706682.

  Monomethanesulfonic acid addition salts of compound (III) and preferred crystal forms thereof are disclosed in PCT patent application WO 99/03854 published on Jan. 28, 1999.

  Also included are pharmaceutically acceptable salts thereof, corresponding racemates, diastereoisomers, enantiomers, tautomers, and corresponding crystal modifications of the above compounds, if any, such as therein. Solvates, hydrates and polymorphs disclosed in. The compounds used as active ingredients in the combinations of the invention can be prepared and administered as described in the respective cited references. Also within the scope of the invention is a combination of more than two separate active ingredients as specified above, i.e. a pharmaceutical combination within the scope of the invention comprises three or more active ingredients. May be included.

In accordance with certain discoveries of the present invention, the following are provided:
1.
A pharmaceutical combination comprising: a) a pyrimidylaminobenzamide compound of formula (I); and b) imatinib of formula (III).

2. A method for the treatment or prophylaxis of a proliferative disease in a subject in need of treatment, wherein the subject is treated, for example simultaneously or sequentially, with a therapeutically effective amount of a pyrimidyl of formula (I), for example as described above. A method comprising co-administering an aminobenzamide compound and imatinib of formula (III).
Examples of proliferative diseases include, for example, tumors, with GIST being particularly preferred.

3. For example, the pharmaceutical combination defined in 1) above for use in the method defined in 2) above.

4. A pharmaceutical combination as defined in 1) above for use in the manufacture of a medicament for use in the method defined in 2) above.

5.
A pharmaceutical combination preferably comprising: a) a compound of formula (II); and b) imatinib of formula (III).

6. A method for the treatment or prophylaxis of a proliferative disease in a subject in need of treatment, said subject comprising, for example, simultaneously or sequentially, a therapeutically effective amount of a pyrimidyl of formula (II), for example as described above A method comprising co-administering an aminobenzamide compound and imatinib of formula (III).

7. A pharmaceutical combination as defined in 5) above for use in the manufacture of a medicament for use in the method as defined in 6) above.

8. A pharmaceutical combination as defined in 5) above for use in the manufacture of a medicament for use in the method defined in 6) above.

  The usefulness of the combinations of the present invention in the methods specified above can be demonstrated in animal test models as well as clinically, for example, according to the methods described below.

A. Combination treatment Suitable clinical trials are, for example, open label, dose escalation trials in patients with proliferative diseases, especially GIST. Such a test particularly demonstrates the synergy of the active ingredients of the combination of the invention. The beneficial effect on GIST can be determined directly via the results of these tests known per se to those skilled in the art. Such a test is particularly suitable for comparing the effects of monotherapy using the active ingredient and the combination of the present invention. Preferably, the dose of drug (a), such as compound (I) or preferably compound (II), is increased until the maximum tolerated dose is reached, and drug (b) is administered at a fixed dose. Alternatively, drug (a) is administered at a fixed dose and the dose of drug (b) is increased. Each patient receives medication (a) daily or intermittently. The effect of treatment can be determined in such a test, for example, by evaluation of symptom scores every 6 weeks after 12, 18 or 24 weeks.

  Administration of the pharmaceutical combination of the present invention is beneficial with respect to beneficial effects such as alleviation, delayed progression of symptoms or prevention of symptoms compared to monotherapy where only one of the pharmaceutically active ingredients used in the combination of the present invention is applied. Not only have a synergistic therapeutic effect, but also lead to surprising and beneficial effects such as fewer side effects, improved quality of life or reduced morbidity.

  Further beneficial is that a low dose of the active ingredients of the combination of the present invention can be used, for example, not only is the dose required often small but can also be applied less frequently, which can reduce the event or severity of the side effects . This meets the patient's desires and requirements to be treated.

  As used herein, the terms “co-administration” or “combination administration” and the like are meant to include administration of a selected plurality of therapeutic agents to a single patient, and the agents are not necessarily administered by the same route of administration or simultaneously. It is intended to include treatment regimens that are not.

  It is an object of the present invention to provide a pharmaceutical composition comprising a certain amount of a combination of the present invention that is a therapeutically effective amount for the targeting or prevention of proliferative diseases, especially GIST. In the composition, agent (a) and agent (b) may be administered together, alternately or separately, in one combined unit dosage form, or in two separate unit dosage forms. The unit dosage form may also be a fixed combination.

  Pharmaceutical composition for separate administration of drug (a) and drug (b) according to the invention, or pharmaceutical composition for administration in a fixed combination, ie at least two combination partners (a) And a single galenic composition containing (b) can be produced by a method known per se and is suitable for oral or rectal enteral administration to mammals including humans (warm-blooded animals), for example, the above-mentioned A therapeutically effective amount of at least one pharmacologically active combination partner alone or in particular one or more pharmaceutically acceptable carriers or dilutions suitable for enteral or parenteral administration In combination with the agent.

  Suitable pharmaceutical compositions contain, for example, from about 0.1% to about 99.9%, preferably from about 1% to about 60%, active ingredient (s). Pharmaceutical preparations for combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. Unless otherwise stated, these are prepared in a manner known per se, for example by means of conventional mixing, granulation, sugar coating, dissolution or lyophilization methods. It will be appreciated that the content of combination partners included in the individual doses of each dosage form need not constitute an effective amount per se, since the required effective amount can be reached by the administration of multiple dosage units.

  In particular, a therapeutically effective amount of each combination partner of the combination of the present invention may be administered simultaneously or sequentially and in any order, and these components may be administered separately or as a fixed combination. For example, the method of preventing or treating a proliferative disease of the present invention comprises (i) first administering a free or pharmaceutically acceptable salt form of the agent (a), and (ii) free or pharmaceutically acceptable. The salt forms of the drug (b) are administered simultaneously or in any order in combination in a therapeutically effective amount, preferably in a synergistically effective amount, eg daily or intermittent corresponding to the amounts described herein Administer by volume. The individual combination partners of the combination of the invention may be administered separately at different times during the course of treatment, or simultaneously in divided or single combination forms. Furthermore, the term administration also encompasses the use of prodrugs of the combination partner that convert in vivo to the combination partner itself. The present invention should therefore be understood to encompass all such regimes of simultaneous or alternating administration, and the term “administering” should be construed accordingly.

  The effective amount of each combination partner used in the combinations of the invention can vary depending on the particular compound or pharmaceutical composition used, the mode of administration, the condition being treated, and the severity of the condition being treated. Therefore, the administration regimen of the combination of the present invention is selected according to various factors including the route of administration and the kidney and liver function of the patient. The ordinary skill clinician or physician can readily determine and prescribe the effective amount of a single active ingredient required to alleviate, recover or stop progression of this condition. Optimal details to achieve a range of active ingredient concentrations that produce non-toxic effects requires a dosing regimen based on the kinetics of the active ingredient's availability at the target site.

  The daily dose of agent (a) or (b) will, of course, depend on a variety of factors including, for example, the compound selected, the particular condition to be treated and the desired effect.

  Preferably the compound of formula (I), drug (a) is administered orally, preferably at a daily dose of 1-300 mg / kg body weight, or for most large primates, 50-5000, preferably 500-3000 mg. Dosage daily. A preferred oral daily dose is 1-75 mg / kg body weight, or for most large primates, a daily dose of 10-2000 mg, as a single dose or in multiple doses such as twice daily. Divide and administer.

  Drug (b) may be administered to a human in a daily dose ranging from 0.5 to 1000 mg. Suitable unit dosage forms for oral administration contain from about 0.1 to 500 mg of active ingredient together with one or more pharmaceutically acceptable diluents or carriers.

  In general, however, satisfactory results have been obtained as a single dose or in divided doses of about 0.03 to 5 mg / kg / day, in particular 0.1 to 5 mg / kg / day, for example 0.1 to 2.5 mg / kg. Achieved with a daily dose of drug (b) on the order of / day. Drug (a) and drug (b) can be administered by any conventional route, in particular enterally, for example orally, for example in the form of tablets, capsules, drinking solutions or parenterally, for example injectable solutions or It can be administered with one or more pharmaceutically acceptable diluents or carriers in the form of a suspension.

  Administration of the pharmaceutical combination of the present invention is beneficial with respect to beneficial effects such as alleviation, delayed progression of symptoms or prevention of symptoms compared to monotherapy where only one of the pharmaceutically active ingredients used in the combination of the present invention is applied. Not only have a synergistic therapeutic effect, but also lead to surprising and beneficial effects such as fewer side effects, improved quality of life or reduced morbidity.

  It is further beneficial to be able to use small doses of the active ingredients of the combination of the present invention, e.g. not only in small doses required, but also to be applied less frequently, or to reduce the event or severity of side effects Can be used. This meets the patient's desires and requirements to be treated.

B. Diseases to be treated The term “proliferative disease” includes, but is not limited to, tumors, psoriasis, restenosis, sclerodermitis and fibrosis.

  The term hematological malignancy means in particular leukemia, especially leukemia expressing Bcr-Abl, c-Kit or Flt-3, and chronic myeloid leukemia and acute lymphocytic leukemia (ALL), especially Philadelphia Including but not limited to chromosome positive acute lymphocytic leukemia (Ph + ALL) as well as STI57I resistant leukemia.

  The term “solid tumor disease” includes inter alia ovarian cancer, breast cancer, colon and generally gastrointestinal cancer, cervical cancer, lung cancer, eg small cell lung cancer and non-small cell lung cancer, head and neck cancer, bladder cancer, prostate cancer or Kaposi's sarcoma Means.

  The inventive combinations that inhibit the described protein kinase activity, in particular the tyrosine protein kinases described above and below, can therefore be used for the treatment of protein kinase dependent diseases. Protein kinase-dependent diseases are inter alia proliferative diseases, preferably benign or especially malignant tumors (e.g. kidney, liver, adrenal, bladder, breast, stomach, ovary, colon, rectum, prostate, pancreas, lung, vagina or thyroid carcinoma). Sarcomas, glioblastomas and various tumors of the head and neck, and leukemia). They can lead to tumor remission and prevention of tumor metastasis formation and proliferation (including micro) metastasis. In addition, they can be used in epithelial hyperproliferation (eg psoriasis), benign prostatic hyperplasia, and especially in the treatment of neoplasms of epithelial character, eg breast carcinoma. It is also possible to use the combinations according to the invention for the treatment of diseases of the immune system, as long as several, especially individual tyrosine protein kinases are involved; It can also be used to treat diseases of the central or peripheral nervous system that involve signaling by at least one tyrosine protein kinase selected from those described.

  In chronic myelogenous leukemia (CML), a reciprocally balanced chromosomal translocation in hematopoietic stem cells (HSC) produces the BCR-ABL hybrid gene. The latter encodes an oncogenic Bcr-Abl fusion protein. While ABL encodes a tightly regulated protein tyrosine kinase that has an essential role in the control of cell proliferation, adhesion and apoptosis, the BCR-ABL fusion gene is encoded as a constitutively activated kinase, which is HSC Is transformed to produce a phenotype that exhibits a deregulated clonal expansion, reduced adhesion to bone marrow stroma and a reduced apoptotic response to mutagenic stimuli, which progressively increases more malignant transformation It is possible to accumulate in The resulting granulocytes cannot develop into mature lymphocytes and are released into the circulation, leading to a lack of mature cells and increased susceptibility to infection. ATP competitive inhibitors of Bcr-Abl prevent kinases from accumulating in mitogenic and anti-apoptotic pathways (eg P-3 kinase and STAT5), resulting in fat in BCR-ABL phenotype cells and hence It is described as providing an effective treatment for CML. The combination according to the invention is therefore particularly suitable for the treatment of diseases associated with its overexpression, in particular leukemias such as leukemias such as CML or ALL.

  The combination of the present invention primarily inhibits the growth of defects, and thus, for example, many diseases associated with deregulated angiogenesis, especially ocular neovascularization, especially retinopathy such as diabetic retinopathy or age-related macular Degeneration, psoriasis, hemangioblastoma, eg hemangioma, mesangial cell proliferative disorder, eg chronic or acute kidney disease, eg diabetic nephropathy, malignant nephrosclerosis, thrombotic microvascular syndrome or transplant rejection, or especially inflammation Kidney disease, such as glomerulonephritis, especially mesangial proliferative glomerulonephritis, hemolytic uremic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmune disease, diabetes, endometrium Diseases, chronic asthma, and especially neoplastic diseases (solid tumors as well as leukemias and other hematological malignancies) such as breast cancer, colon cancer, lung cancer (especially Cell lung cancer), it is effective against prostate cancer or Kaposi's sarcoma. The combinations of the present invention inhibit tumor growth and are particularly suitable for preventing metastatic spread of tumors and the growth of micrometastasis.

  The present invention relates to a method for treating myeloma, particularly myeloma resistant to conventional chemotherapy. The term “myeloma” as used herein refers to a tumor composed of the types of cells normally found in the bone marrow. As used herein, the term “multiple myeloma” refers to multiple bone marrow tumor lesions associated with a wide range of osteolytic lesions that lead to bone pain, pathological fractures, hypercalcemia, and orthochromic orthocytic anemia. It refers to scattered malignant neoplasms of plasma cells characterized by secretion of M component (monoclonal immunoglobulin fragment). Multiple myeloma cannot be cured by the use of conventional and high dose chemotherapeutic agents. The present invention relates to a method for treating myeloma, particularly myeloma resistant to conventional chemotherapy.

Activating mutations in platelet-derived growth factor receptor alpha (PDGFRA) have been reported in a subset of mutant stem cell factor receptor, gastrointestinal stromal tumors that do not express c-KIT (GIST) patients. The responsiveness of the mutant PDGFRA positive GIST to imatinib depends on the position of the PDGFRA mutation: for example, the V561D near-membrane domain is more sensitive to imatinib than the D842V kinase domain mutation. In this example, the effects of Compound (II) and Imatinib [Compound (III)] on two GIST-related PDGFRA mutants, V561D and D842V, which have different sensitivities to imatinib are tested.

Cell lines and cell cultures: Construction of D842V, V561D and wild type (wt) PDGFRA cDNA cloned into pcDNA3.1 (obtained from MC Heinrich, Oregon Health & Science University Cancer Institute, Portland, OR) was electroporated. Ba / F3 cells are stably transfected with and the cells are selected for neomycin resistance and IL3-independent growth. Total cells supplemented with 10% fetal calf serum (FCS; Harlan Bioproducts, Indianapolis, IN), 1% glutamine, and penicillin / streptomycin at a concentration of 5 × 10 ⁵ cells / mL at 37 ° C. in the presence of 5% CO _2. Culture in cellgro RPMI 1640 medium (Mediatech, Inc. Herndon, VA). Parental Ba / F3 cells or wt-PDGFRA-Ba / F3 cells are cultured with 15% WEHI conditioned medium as a source of IL-3. All transfected cells are cultured in medium supplemented with 1 mg / mL G418.

Antibodies and immunoblotting: Anti-p-Tyr (clone 4G10, Upstate Biotechnology, NY) is used for immunoblotting at 1: 1000. PDGFRA antibody (C-20, Santa Cruz Biotechnology, CA) is used for immunoblotting at 1: 200. Protein lysate preparation and immunoblotting are performed as previously described. Weisberg et al., Cancer Cell 2002; 1: 433-443.

Proliferation test: The trypan blue exclusion assay has been previously described (Weisberg et al., Cancer Cell 2002; 1: 433-443) and is used for all proliferation tests. Compound II and imatinib are added to either D842V- or V561D-PDGFRA-Ba / F3 cells in a fixed ratio at the same time. Dose response curves are generated and the combination index is calculated as described in Weisberg et al., Cancer Cell 2005; 7: 129-141.

Mouse studies and in vivo imaging: D842V-PDGFRA-Ba / F3 cells were transduced with a retrovirus encoding firefly luciferase (MSCV-Luc), selected with puromycin at a concentration of 0.5 μg / mL, and D842V-PDGFRA -Produce a Ba / F3-luciferase (luc +) cell line. Cells without mycoplasma and virus contamination are resuspended in Hank's balanced salt solution (HBSS; Mediatech, Inc., VA) and then administered iv to mice. 200 mg of the solution of Compound II is dissolved in 1.0 mL NMP to obtain a clear solution, which is diluted daily with 9.0 mL PEG300 and administered. Placebo mice receiving vehicle for Compound II are administered at 30-45 minute intervals.

  Male NCR nude mice (5-6 weeks old; Taconic, NY) are administered a total of 600,000 D842V-PDGFRA-Ba / F3-luc + cells by tail vein injection. Mice are imaged and systemic oral quantification as previously described (Armstrong et al., Cancer Cell 2003; 3: 173-183). Baseline imaging one day after tumor cell inoculation is used to establish a treatment cohort with a suitable tumor burden. A cohort of mice is treated with oral administration of vehicle, 150 mg / kg / day Compound II (formulated as above; total treatment 6 days). Repeated imaging is performed at various intervals.

Combined effect of compound II and imatinib: D842V-PDGFRA-Ba / F3:
The combination of Compound II and imatinib is tested against D842V-PDGFRA-Ba / F3 cells. Overall, a positive combination effect is observed between compound II and imatinib. Calcusyn analysis of the combined effect of Compound II and imatinib suggests a synergistic to nearly additive effect (ED ₂₅ -ED ₇₅ ) across the dose range, with antagonism at ED ₉₀ (Table I).

Combination effect of Compound II and Imatinib: V561D:
The combined effect of Compound II and imatinib is evaluated against V561D-PDGFRA-Ba / F3. In general, both combinations lead to varying degrees of antagonism in the V561D-PDGFRA-Ba / F3 cell line over the dose range (Table I).

Claims (2)

4-methyl-3-[[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) Phenyl] benzamide or a pharmaceutically acceptable salt thereof, and the formula

Of imatinib or a pharmaceutically including acceptable salt thereof, for the treatment combination of gastrointestinal stromal tumors with mutations V561D or D842V in PDGFRA,. For the manufacture of a medicament for the treatment of gastrointestinal stromal tumors with mutations V561D or D842V in PDGFRA, wherein

4-methyl-3- [[ 4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) Phenyl] benzamide, or a pharmaceutically acceptable salt thereof, and the formula

Of imatinib, or a pharmaceutically acceptable salt combination thereof.